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Am J Med Genet B Neuropsychiatr Genet. 2019 Jan;180(1):55-67. doi: 10.1002/ajmg.b.32707. Epub 2018 Dec 7.

The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2.

Author information

1
Vanderbilt University Medical Center, Nashville, Tennessee.
2
University of California, San Diego, California.
3
University of Colorado School of Medicine, Aurora, Colorado.
4
Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
5
Greenwood Genetic Center, Greenwood, South Carolina.
6
Boston Children's Hospital, Boston, Massachusetts.
7
Cincinnati Children's Hospital, Cincinnati, Ohio.
8
Gilette Children's Specialty Healthcare, St. Paul, Minnesota.
9
Rush University Medical Center, Chicago, Illinois.
10
Washington University School of Medicine, St. Louis, Missouri.
11
University of California, San Francisco Benioff Children's Hospital Oakland, Oakland, California.
12
Baylor College of Medicine, Houston, Texas.
13
University of Alabama at Birmingham, Birmingham, Alabama.

Abstract

Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome (RTT), primarily in girls. It had been suspected that mutations in Methyl-CpG-binding protein 2 (MECP2) led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified 30 males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment. Two males with a somatic mutation in MECP2 had classic RTT. Of the remaining 28 subjects, 16 had RTT-causing MECP2 mutations, 9 with mutations that are not seen in females with RTT but are likely pathogenic, and 3 with uncertain variants. Two subjects with RTT-causing mutations were previously diagnosed as having atypical RTT; however, careful review of the clinical history determined that an additional 12/28 subjects met criteria for atypical RTT, but with more severe clinical presentation and course, and less distinctive RTT features, than females with RTT, leading to the designation of a new diagnostic entity, male RTT encephalopathy. Increased awareness of the clinical spectrum and widespread comprehensive genomic testing in boys with neurodevelopmental problems will lead to improved identification.

KEYWORDS:

MECP2; Rett syndrome; encephalopathy; genetics; male; neurodevelopmental disorders

PMID:
30536762
DOI:
10.1002/ajmg.b.32707

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